Table 2.
The chromosome aberrations related to pretesticular male infertility: from the first observation to the report
| Indications for genetic test | Genetic condition | Frequency | Test | Chromosome/genetic alterations | ART | Inheritance | Antenatal test | Differential diagnosis | Refs. |
|---|---|---|---|---|---|---|---|---|---|
| Hypergonadotropic hypogonadism, ↑FSH ↑LH ↓T, azoospermia, oligozoospermia; small testes, infertility, gynecomastia; neurocognitive deficits; metabolic syndrome, type 2 diabetes. Approximately 10% of these subjects have spermatozoa in the ejaculate, and in 30–50% of cases there is intratesticular spermatogenesis | Klinefelter’s syndrome | 1/660 newborns; > 5% in severe oligozoospermia; 10% in azoospermia | Karyotype |
47,XXY (85–90%) 46,XY/47,XXY mosaicism (6–7%) 46,XX/47,XXY or multiple X aneuploidy (3–8%) |
✓ Testicular sperm retrieval + ICSI | De novo mutation | NA | 46,XX testicular DSD | [11, 12] |
| Short stature; gynecomastia, male external genitalia, small testes, cryptorchidism, hypospadias, infertility, ↑FSH ↑LH↓T; azoospermia/oligozoospermia | Nonsyndromic 46,XX Testicular Disorders of Sex Development (De la Chapelle syndrome) | 1/20.000; 0,9% in azoospermia; 1–3% normospermia | FISH or CMA | SRY+ XX (80–90%) | ✗ Testicular sperm retrieval; ✓ heterologous fertilization | AD | ✓ | Syndromic forms of 46,XX testicular DSD; 45X/46,XY; 47,XXY; 46,XX; sex chromosome mosaicisms; Prenatal exposure of 46,XX fetuses to androgens | [13] |
| Penoscrotal hypospadias, cryptorchidism, infertility; ↑FSH ↑LH↓T; azoospermia/oligozoospermia | SRY− XX (< 10%) | Unknown | ✓ | ||||||
| Short stature; small testes, infertility; ↑FSH ↑LH↓T; azoospermia/oligozoospermia | CMA or molecular diagnostic by PCR | CNV or rearrangements in SOX9, SOX3, RSPO1 and WNT4 (rare) | ✓AD for SOX9; AR for RSPO1 or WNT4 | ✓ | 46,XX; 46,XY disorders of sex development | [14–18] | |||
| Tall stature, delayed development of speech, language or motor skills, autism spectrum disorder, hypotonia, motor tics, clinodactyly, scoliosis, attention deficit hyperactivity disorder; ↑FSH normal or ↓T; from normal to azoospermia; from 0.57 to 77.8% sperm mosaicism, a- or hyper diploidy | Double Y syndrome (Jacobs syndrome) | 1/1.000; 0.4% in oligozoospermia | Cytogenetics tests | 47,XYY; 46,XY/47,XYY mosaics | ✓IVF or ICSI in case of oligospermic patients | Does not have a clear pattern of inheritance | ✓ | 46,XY | [14, 19] |
| Subfertility or uneventful andrological history; oligozoospermia | Balanced structural chromosome aberrations | 5% of infertile men | FISH | t(SRY; X); der(13, 14); der(14, 21); der(14, 15) | ✓ | NA | ✓ PGT | Other causes of oligozoospermia | [20] |
Database sources: NIH, OMIM and OrphaNet
✓, yes; ✗, no; NA, not applicable; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; FISH, fluorescence in situ hybridization; PGT: preimplantation genetic testing; CMA, chromosomal microarray analysis